Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer

Abstract

Triple-negative breast cancer (TNBC) accounts for ∼20% of cases and contributes to basal and claudin-low molecular subclasses of the disease. TNBCs have poor prognosis, display frequent mutations in tumor suppressor gene p53 (TP53), and lack targeted therapies. The MET receptor tyrosine kinase is elevated in TNBC and transgenic Met models (Met mt ) develop basal-like tumors. To investigate collaborating events in the genesis of TNBC, we generated Met mt mice with conditional loss of murine p53 (Trp53) in mammary epithelia. Somatic Trp53 loss, in combination with Met mt , significantly increased tumor penetrance over Met mt or Trp53 loss alone. Unlike Met mt tumors, which are histologically diverse and enriched in a basal-like molecular signature, the majority of Met mt tumors with Trp53 loss displayed a spindloid pathology with a distinct molecular signature that resembles the human claudin-low subtype of TNBC, including diminished claudins, an epithelial-tomesenchymal transition signature, and decreased expression of the microRNA-200 family. Moreover, although mammary specific loss of Trp53 promotes tumors with diverse pathologies, those with spindloid pathology and claudin-low signature display genomic Met amplification. In both models, MET activity is required for maintenance of the claudin-low morphological phenotype, in which MET inhibitors restore cell-cell junctions, rescue claudin 1 expression, and abrogate growth and dissemination of cells in vivo. Among human breast cancers, elevated levels of MET and stabilized TP53, indicative of mutation, correlate with highly proliferative TNBCs of poor outcome. This work shows synergy between MET and TP53 loss for claudin-low breast cancer, identifies a restricted claudin-low gene signature, and provides a rationale for anti-MET therapies in TNBC.Met RTK | EMT | mouse model | gene expression

Specificity Protein 1 (Sp1) Maintains Basal Epithelial Expression of the miR-200 Family

“…We have found that Sp1 can also activate the miR-200cϳ141 promoter; however this effect may be indirect as binding of endogenous Sp1 has not been detected in its promoter region. Interestingly, in breast cancer, p53 reduction or mutation can augment loss of miR-200 levels, but penetrance is often incomplete and is dependent on activation of other signaling pathways (such as HGF signaling via MET) for a full EMT (60,61). This would be in keeping with the notion that activation of mesenchymal signaling pathways are needed to sustain repression of miR-200.…”

Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

“…Upregulation of mesenchymal biomarkers and Met activation have both been associated separately with prognosis in several tumor types (6,(31)(32)(33) and coexistence of both markers with stemness (34). One could hypothesize that the presence of a subset of cells with these markers in SCLC at diagnosis could predict the enrichment of this chemoresistant population at progression after chemotherapy and, therefore, explain the poor prognosis of these patients in our study.…”

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

“…9 In HCC827 GR2 cells, AXL kinase expression was too low for detection by western blotting, and although HCC4006 GR3 cells clearly expressed AXL, they did not require the kinase for survival. In addition, while some reports show that aberrant Met activation via mutation or ligand activity secreted by stromal cells induces EMT and promotes invasion of carcinoma cells in many types of cancers, [35][36][37] the GR cells characterized in this study did not depend on Met signaling for survival. This is in line with previous work by others showing that EGFR TKI-resistant EGFR-mutant cells with an EMT phenotype were uniformly not dependent on Met kinase.…”